This application was submitted in response to RFA DK-06-504 to continue the efforts of the Inflammatory Bowel Disease Genetics Consortium (IBDGC) and our role as a Genetic Research Center (GRC) with the central goal of identifying susceptibility genes contributing to the pathogenesis of inflammatory bowel disease (IBD). This will be accomplished through the following specific aims. Specific Aim 1: Expansion, development and management of Consortium resources is required to enhance the capacity to identify genetic variation contributing to the pathogenesis of IBD. This will be accomplished through GRC recruitment of additional IBD cases with a focus on early onset, ulcerative colitis (UC), African-American Crohn's disease (CD) and UC, and Puerto Rican CD and UC cases. Extensive clinical data will be collected on recruited subjects and biospecimens (EBV-transformed lymphoblastoid cell lines, DMA, serum, whole blood) will be ascertained and stored at the NIDDK Genetics Repository for use by the Consortium, individual GRCs and outside investigators. Specific Aim 2: To identify genetic variation that contributes to IBD susceptibility through a variety of complementary approaches including genome-wide association (GWA) and follow-up of GWA results as the primary approach in European ancestry samples;and comparative association studies and mapping by admixture linkage disequilibrium in African-American and Puerto Rican samples, and genome-wide association in African-American samples. Specific Aim 3: To build a risk model of IBD through understanding genetic influence on variations in phenotypic expressivity, gene pathway analysis, and gene-gene and gene-environmental interactions. With the expanded NIDDK Genetics Repository outlined in this proposal, the Consortium will be in a position to use clinical subphenotypes, gene pathways, gene-gene and gene-environment interactions to further understand the genetic basis of IBD. Specific Aim 4: This GRC will continue to lead efforts to identify the IBD susceptibility gene(s) in the IBD6 region on chromosome 19 using the resources of the IBDGC.IBD is a chronic inflammatory disease of the gastrointestinal tract which primarily affects young people and is characterized by long-term illness and the need for potent medical therapy and substantial surgical therapy. The work of the IBDGC and this GRC will enable us to identify important predisposing and disease modifying genes contributing to the pathogenesis of IBD which has the promise to: (1) identify persons at risk for disease, (2) predict disease course, (3) aid in selection of treatment, (4) understand pathophysiologic mechanisms such that novel preventive and therapeutic interventions can be developed. Advances in IBD gene identification and methodologic approaches may also be applicable to other complex genetic disorders.